Study of Low-Intensity Conditioning for Allogeneic Stem Cell Transplant

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00143845
• Collaborator: (none)
• Enrollment: 54
• Location: 1
• Arm: 1
• Duration (Months): 118.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether a reduced intensity conditioning regimen for stem cell transplant with donor cells will allow the donor cells to be effective without causing health problems.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma; Lymphocytic Leukemia, Chronic; Lymphoma, Low-Grade	Procedure: Reduced intensity conditioning; Procedure: Rapid immunosuppressive taper; Procedure: Prophylactic donor leukocyte infusions	Phase 2

Detailed Description

In this research study patients will receive dosages of chemotherapy that are lower than the usual dosages. The study will determine whether a shorter duration of immunosuppression will permit the donor cells to be effective against the cancer without causing more severe GVHD (Graft Versus Host Disease). Also to be determined is whether the patient's cancer can be prevented from relapsing after blood stem cell transplant by using prophylactic treatment, giving a donor leukocyte infusion BEFORE a relapse happens.

In this research study samples of blood and bone marrow will be analyzed. These samples will be examined to study the cellular production of inflammatory cytokine levels in attempt to be able to predict which patients will have complications like GVHD or relapse.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Adjuvant Cellular Immunotherapy for High-Risk Hematologic Malignancy After Reduced Intensity Allogeneic Stem Cell Transplantation
• Study Start Date: Apr 1, 2003
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Immunosuppression Taper Reduced intensity conditioning consisting of Busulfan and Fludarabine(fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy), followed by a rapid immunosuppressive taper of Tacrolimus (0.06 mg/kg q12h, PO, Days -7 to +28), Methotrexate (5 mg/m2, IV, Days +1, +3, +6, +11) and Mycophenolate Mofetil (10 mg/kg every 8 hours, PO, Days -6 to +7).

Procedure: Reduced intensity conditioning; Busulfan and Fludarabine regimen; Procedure: Rapid immunosuppressive taper; Taper of Tacrolimus, Methotrexate and Mycophenolate Mofetil; Procedure: Prophylactic donor leukocyte infusions; If the patient has GVHD overall grade 0-1 or skin grade 1 on day +100, then 5 x 107 CD3+ cells/kg recipient weight are given.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Acute Graft Versus Host Disease (GVHD) Grades 2-4 [100 days]

   The primary objective of this study was to establish the rate of acute GVHD following prophylactic cellular immunotherapy after allogeneic hematopoietic stem cell therapy using low intensity conditioning for high-risk hematological malignancies. Glucksberg staging was used for organ grading of GVHD. Clinical GVHD was assessed as follows: Grade 0: No stage 1-4 of any organ Grade 1: Stage 1-2 rash and no liver or gut involvement Grade 2: Stage 3 rash, or Stage 1 liver involvement, or Stage 1 GI Grade 3: Stage 0-3 skin with Stage 2-3 liver, or Stage 2-4 GI Grade 4: Stage 4 skin rash, or Stage 4 liver involvement

2. Percentage of Participants With Progression Free Survival [two years]

   The second primary objective was to determine the percentage of participants with progression free survival following prophylactic cellular immunotherapy after allogeneic hematopoietic stem cell therapy using low intensity conditioning for high-risk hematological malignancies. We define disease progression as disease recurrence within 180 days of transplant.

Secondary Outcome Measures

1. Percentage of Patients Alive at 2 Years [2 Years]

   To estimate the overall survival of patients progression following prophylactic cellular immunotherapy after allogeneic hematopoietic stem cell therapy using low intensity conditioning for high-risk hematological malignancies.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Patient Inclusion Criteria:

To be eligible a patient MUST meet at least one of the next 4 criteria

• Any patient aged 55 years or older with a hematological malignancy for which allogeneic transplant is considered an appropriate treatment, AND/OR

• Any patient, regardless of age, with a hematologic malignancy for which allogeneic transplant is considered an appropriate treatment and the patient is not eligible for a conventional myeloablative transplant because of organ dysfunction AND/OR

• Any patient, regardless of age, who has relapsed following prior autologous or allogeneic transplant for a hematologic malignancy AND/OR

• Any patient, regardless of age, with one of the following hematological malignancies:

1. Multiple myeloma

2. refractory to or failure following conventional chemotherapy such as VAD (Vincristine, Adriamycin and Dexamethasone), pulse decadron, or alkylating agents, or

3. chromosomal abnormality associated with poor prognosis by cytogenetics or FISH probe.

4. Chronic lymphocytic leukemia patients, Rai stage 3 or 4 and relapsed following/refractory to alkylating agents or nucleoside analog therapy

5. Low grade lymphoma (small lymphocytic, follicular small cleaved cell, or follicular mixed small cleaved and large cell) that is either relapsed or refractory provided the disease is NOT rapidly progressive, NOT bulky, and no mass exceeds 5 cm in greatest dimension.

To be eligible a patient MUST meet all of the following criteria

• In addition to the above criteria ALL patients must meet the following minimum organ function:

1. Cardiac: Ejection fraction at least 30%.

2. Renal: Adequate renal function as defined by creatinine < 2.0mg OR creatinine clearance >40 mg/min by 24-hour urine collection or GFR (Glomerular Filtration Rate. (Gender and age-adjusted creatinine clearance >40ml/min by Gault-Cockroft 55 is acceptable for adults: (140 - age) x weight/72 x Scr [x 0.85 if female]).

3. Pulmonary: FEV1 and FVC >60%.

4. Hepatic: Total bilirubin <2.0 and AST (Aspartate Aminotransferase)/ALT (Alanine Transaminase) < 3X institutional normal for age.

5. Performance (adults): Karnofsky score must be at least 60; for pts. under 16, Lansky score must be at least 60.

• Availability of a 5/6 or 6/6 HLA A, B, and DR identical relative who is willing and able to donate allogeneic stem cells. Serological, low resolution or mid resolution molecular typing will determine the degree of match for HLA (Human Leukocyte Antigen) class I regardless of high resolution DNA typing results. High resolution typing will be used to determine the degree of match for HLA-DR.

• No untreated or uncontrolled invasive infections. Patients still under therapy for presumed or proven infection are eligible provided there is clear evidence (radiologic and/or culture) that the infection is well controlled. Patients under treatment for infection will be enrolled only after clearance from the Principal Investigator.

• Not pregnant

Patient Exclusion Criteria:

• acute leukemia

• HIV positive patients not eligible

• Any physical or psychological condition that, in the opinion of the investigator, would pose unacceptable risk to the patient

• Pregnant

Donor Inclusion Criteria:

• 5/6 or 6/6 HLA match for HLA-A, B, and DR

• Age 3-70 years, good general health

• No contraindication to G-CSF (Granulocyte Colony-Stimulating Factor)stimulation

• No contraindication to leukapheresis of peripheral blood stem cells

• Good general health

Donor Exclusion Criteria:

• HIV positive or history of HIV risk factors

• Presence of other diseases transmissible by blood that pose unacceptable risk to the study subject.

• Pregnant

• Medical or psychological conditions that would make the donor unlikely to tolerate G-CSF - injections or leukapheresis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Michigan	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: John E. Levine, MD, MS, The Univeristy of Michigan

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT00143845
• Other Study ID Numbers: UMCC 2-61
• First Posted: Sep 2, 2005
• Last Update Posted: Mar 8, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Multiple Myeloma; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Immunosuppressive Agents

Study Results

Participant Flow

Arm/Group Title	Immunosuppression Taper
Arm/Group Description	Reduced intensity conditioning consisting of Busulfan and Fludarabine(fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy), followed by a rapid immunosuppressive taper of Tacrolimus (0.06 mg/kg q12h, PO, Days -7 to +28), Methotrexate (5 mg/m2, IV, Days +1, +3, +6, +11) and Mycophenolate Mofetil (10 mg/kg every 8 hours, PO, Days -6 to +7).
Period Title: Overall Study
STARTED	54
COMPLETED	54
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Immunosuppression Taper
Arm/Group Description	Reduced intensity conditioning consisting of Busulfan and Fludarabine(fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy), followed by a rapid immunosuppressive taper of Tacrolimus (0.06 mg/kg q12h, PO, Days -7 to +28), Methotrexate (5 mg/m2, IV, Days +1, +3, +6, +11) and Mycophenolate Mofetil (10 mg/kg every 8 hours, PO, Days -6 to +7).
Overall Participants	45
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Gender (Count of Participants)
Female	22 48.9%
Male	23 51.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Acute Graft Versus Host Disease (GVHD) Grades 2-4
Description	The primary objective of this study was to establish the rate of acute GVHD following prophylactic cellular immunotherapy after allogeneic hematopoietic stem cell therapy using low intensity conditioning for high-risk hematological malignancies. Glucksberg staging was used for organ grading of GVHD. Clinical GVHD was assessed as follows: Grade 0: No stage 1-4 of any organ Grade 1: Stage 1-2 rash and no liver or gut involvement Grade 2: Stage 3 rash, or Stage 1 liver involvement, or Stage 1 GI Grade 3: Stage 0-3 skin with Stage 2-3 liver, or Stage 2-4 GI Grade 4: Stage 4 skin rash, or Stage 4 liver involvement
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

54 patients were enrolled however 9 patients did not receive planned donor lymphocyte infusion. 45 patients were analyzed.

Arm/Group Title	Immunosuppression Taper
Arm/Group Description	Reduced intensity conditioning consisting of Busulfan and Fludarabine(fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy), followed by a rapid immunosuppressive taper of Tacrolimus (0.06 mg/kg q12h, PO, Days -7 to +28), Methotrexate (5 mg/m2, IV, Days +1, +3, +6, +11) and Mycophenolate Mofetil (10 mg/kg every 8 hours, PO, Days -6 to +7).
Measure Participants	45
Number [percentage of participants]	73 162.2%

2. Primary Outcome

Title	Percentage of Participants With Progression Free Survival
Description	The second primary objective was to determine the percentage of participants with progression free survival following prophylactic cellular immunotherapy after allogeneic hematopoietic stem cell therapy using low intensity conditioning for high-risk hematological malignancies. We define disease progression as disease recurrence within 180 days of transplant.
Time Frame	two years

Outcome Measure Data

Analysis Population Description

54 patients were enrolled however 9 patients did not receive planned donor lymphocyte infusion. 45 patients were analyzed.

Arm/Group Title	Immunosuppression Taper
Arm/Group Description	Reduced intensity conditioning consisting of Busulfan and Fludarabine(fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy), followed by a rapid immunosuppressive taper of Tacrolimus (0.06 mg/kg q12h, PO, Days -7 to +28), Methotrexate (5 mg/m2, IV, Days +1, +3, +6, +11) and Mycophenolate Mofetil (10 mg/kg every 8 hours, PO, Days -6 to +7).
Measure Participants	45
Number [percentage of participants]	35 77.8%

3. Secondary Outcome

Title	Percentage of Patients Alive at 2 Years
Description	To estimate the overall survival of patients progression following prophylactic cellular immunotherapy after allogeneic hematopoietic stem cell therapy using low intensity conditioning for high-risk hematological malignancies.
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

54 patients were enrolled however 9 patients did not receive planned donor lymphocyte infusion. 45 patients were analyzed.

Arm/Group Title	Immunosuppression Taper
Arm/Group Description	Reduced intensity conditioning consisting of Busulfan and Fludarabine(fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy), followed by a rapid immunosuppressive taper of Tacrolimus (0.06 mg/kg q12h, PO, Days -7 to +28), Methotrexate (5 mg/m2, IV, Days +1, +3, +6, +11) and Mycophenolate Mofetil (10 mg/kg every 8 hours, PO, Days -6 to +7).
Measure Participants	45
Number [percentage of participants]	38 84.4%

Adverse Events

Arm/Group Title	Immunosuppression Taper
Arm/Group Description	Reduced intensity conditioning consisting of Busulfan and Fludarabine(fludarabine 150 mg/m2 IV, busulfan 6 mg/kg IV, total lymphoid irradiation 2 Gy), followed by a rapid immunosuppressive taper of Tacrolimus (0.06 mg/kg q12h, PO, Days -7 to +28), Methotrexate (5 mg/m2, IV, Days +1, +3, +6, +11) and Mycophenolate Mofetil (10 mg/kg every 8 hours, PO, Days -6 to +7).
All Cause Mortality
	Immunosuppression Taper
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Immunosuppression Taper
	Affected / at Risk (%)	# Events
Total	42/54 (77.8%)
Cardiac disorders
Hypotension	2/54 (3.7%)
Supraventricular tachycardia	1/54 (1.9%)
Supraventricular arrhythmia	1/54 (1.9%)
Ear and labyrinth disorders
Vertigo	1/54 (1.9%)
Gastrointestinal disorders
Diarrhea	10/54 (18.5%)
Vomiting	4/54 (7.4%)
Nausea	4/54 (7.4%)
Abdominal pain	4/54 (7.4%)
General disorders
Primary Graft Failure	1/54 (1.9%)
Fever	5/54 (9.3%)
Weakness	1/54 (1.9%)
Pyrexia	2/54 (3.7%)
Death	3/54 (5.6%)
Immune system disorders
GVHD	9/54 (16.7%)
GVHD with infectious complications	1/54 (1.9%)
Infections and infestations
Infection	16/54 (29.6%)
Investigations
Lipase	1/54 (1.9%)
Amylase	1/54 (1.9%)
Metabolism and nutrition disorders
Hypomagnesemia	1/54 (1.9%)
Hyperglycemia	1/54 (1.9%)
Musculoskeletal and connective tissue disorders
Back Pain	1/54 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Relapsed Disease	1/54 (1.9%)
Nervous system disorders
Headache	1/54 (1.9%)
Syncope	1/54 (1.9%)
Seizure	1/54 (1.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/54 (1.9%)
Hypoxia	1/54 (1.9%)
Respiratory distress	1/54 (1.9%)
Vascular disorders
DVT	1/54 (1.9%)
Other (Not Including Serious) Adverse Events
	Immunosuppression Taper
	Affected / at Risk (%)	# Events
Total	30/54 (55.6%)
Gastrointestinal disorders
Esophogitis	7/54 (13%)
Mucositis	4/54 (7.4%)
Diarrhea	5/54 (9.3%)
Infections and infestations
Infection	10/54 (18.5%)
Investigations
Creatinine	18/54 (33.3%)
AST	20/54 (37%)
ALT	20/54 (37%)
ALK	15/54 (27.8%)
Metabolism and nutrition disorders
Hypomagnesemia	23/54 (42.6%)
Hyperglycemia	29/54 (53.7%)
Hypoglycemia	6/54 (11.1%)
Hypocalcemia	28/54 (51.9%)
Hypercalcemia	6/54 (11.1%)
Hypermagnesemia	16/54 (29.6%)
Hyperkalemia	14/54 (25.9%)
Hypokalemia	17/54 (31.5%)
Hyponatremia	20/54 (37%)
Hypernatremia	5/54 (9.3%)
Hypoalbuminemia	24/54 (44.4%)
Skin and subcutaneous tissue disorders
Rash	5/54 (9.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.